The present invention provides novel compositions of matter. In particular, the present invention provides novel substituted benzothiazoles, benzimidazoles and benzoxazoles which are useful as inhibitors of the synthesis of leukotrienes and/or as inhibitors of the action of 5-lipoxygenase in mammalian metabolism.
The leukotrienes are a class of unsaturated fatty acid compounds which are derived from arachidonic acid by the action of lipoxygenase. See, e.g., Samuelsson, Trends in Pharmacological Sciences, 5:227 (1980); and Samuelsson, et al., Annu. Rev. Biochem. 47:997-1029 (1978). For a discussion of leukotriene nomenclature, see Samuelsson, et al., Prostaglandins, 19:645 (1980).
The leukotrienes have been discovered as potent constrictors of human bronchi. That is, certain leukotrienes are mediators of the action of slow-reacting substance of anaphylaxis (SRS-A). See, e.g., Dahlen, Nature, 288:484 (1980). These compounds are therefore important mediators of bronchoconstriction in humans.
The role of leukotrienes as agonists in immediate hypersensitivity and other pathological conditions has led to research into inhibitors of leukotriene biosynthesis and leukotriene antagonists. See, e.g., Corey, et al., Tet. Lett. 21:4243 (1980).
Leukotrienes, particularly leukotriene C.sub.4 (LTC.sub.4) and leukotriene D.sub.4 (LTD.sub.4) have been shown to be potent mucus secretagogues. Both LTC.sub.4 and LTD.sub.4 increase the release of mucus from human airways in vitro, Z. Maron, et al., Am. Rev. Respir. Dis. 126, 449-451 (1982); S. J. Coles, et al., Prostaglandins 25, 155-170 (1983), and from canine tracheas in vivo, H. G. Johnson, et al., Int. J. Immunopharmacol. 5, 178 (1983); H. G. Johnson, et al., Prostaglandins 25, 237-243 (1983). Arachidonic acid, metabolic products of arachidonic acid, monohydroxy-eicosatetraenoic acid, and prostaglandins also release mucus from human airway, Z. Maron, et al., J. Clin, Invest. 67, 1695-1702 (1981). LTC.sub.4 was effective in stimulating mucus release in vivo in the cat but not in vitro on cat trachea tissue, A. C. Peatfield, et al., Br. H. Pharmac. 77, 391-393 (1982). J. H. Shelhamer, et al., Chest 81, 36S (1982) summarizes the nature of evidence available suggesting that lipoxygenase products generated by the airways in vitro might be responsible for the augmented mucus release.
O. Cromwell, et al., The Lancet, July 25, 1981, pp. 164-165, identified LTB.sub.4 and LTD.sub.4 in the sputum of cystic fibrosis patients and speculated, therefore, that inhibitors of the lipoxygenase pathway might be capable of reversing the airway obstruction in such patients.
T. Ahmed, et al., Am. Rev. Respir. Dis. 124, 110-114 (1981) demonstrated that FPL 55712, an LTC.sub.4 antagonist when given prior to antigen challenge was effective in reversing the tracheal mucus velocity in patients with a history of bronchial asthma but concluded that the clinical significance of FPL 55712 remains to be demonstrated.
In mammalian metabolism, arachidonic acid is transformed to 12-L-hydroperoxy-5,8,10,14-eicosatetraenoic acid by the action of 12-lipoxygenase. See, Hamberg, et al., Proc. Nat. Acad. Sci. 71:3400-3404 (1974). Similarly, 5-lipoxygenase transforms arachidonic acid into 5-S-hydroperoxy-6,8,11,14-eicosatetraenoic acid. Thus, an agent which inhibits the action of lipoxygenase would be useful in treating or preventing untoward conditions associated with lipoxygenase products.
Therefore, compounds which inhibit the action of lipoxygenase are useful in the treatment of inflammatory conditions where it is desirable to prevent migration of polymorphonuclear leukocytes to the inflammatory site. They are also useful in the treatment of asthma.
Derwent Basic Abstract, Accession Number 91528R, dicloses sulphonyl- and sulphoxylalkylenerhodanines with fungicidal activity.
Derwent Basic Abstract, Accession Number 21800V, dicloses cardiac drugs prepared from corresponding 2-mercapto-benzothiazole derivatives.
Derwent Basic Abstract, Accession Number 29,700, discloses fungicidal, bactericidal alkylbenzothiazolyl sulphones.
Derwent Basic Abstract, Accession Number 00368X, discloses 2-(3-Amino-2-hydroxypropylthio)-benzothiazoles with hypotensive activity.
Derwent Basic Abstract, Accession Number 33201Y, discloses benzene sulphenamides, with heteroaryl-thio, -sulphinyl or -sulphonyl groups, which are cerebral vasodilators without hypotensive effects.
Derwent Basic Abstract, Accession Number 16714W, and Derwent Basic Abstract, Accession Number 33156C, diclose methods for preparing benzothiazolesulphenamide derivatives.
Chemical Abstracts 47:12358c discloses 2,6-substituted benzothiazoles.
Chemical Abstracts 48:4522b discloses 4-(5-, 6-, or 7-)chlorobenzthiazol-2-yl-thiomethane-carboxylic acid.
Derwent Basic Abstract, Accession Number 32993W, discloses pesticidal compositions containing benzoxazole derivatives as active agents, useful in agriculture.
Derwent Basic Abstracts, Accession Number 40,965 and 80522S, disclose methyl-1-naphthyldithiocarbamic acid-2-benzoxazolyl ester which has antimycotic use.
Derwent Basic Abstract, Accession Number 12569, discloses N'-diethylaminoethyl-2-mercapto-benzimidazole derivatives as analgesics.
Derwent Basic Abstract, Accession Number 13,360, discloses 1-(.beta.-diethylaminoethyl)-2-(p-aminophenylthio)-benzimidazole and its hydrochloride salt having analgetic uses.
Derwent Basic Abstract, Accession Number 20,701, discloses N-substituted, 2-thiol derivatives of benzimidazoles which are analgesics.
Derwent Basic Abstract, Accession Number 28,529, discloses 2-phenylthiobenzimidazoles which are analgesics and intermediates.
Derwent Basic Abstract, Accession Number 31,421, discloses pesticidal benzimidazole thiol-carbamates.
Derwent Basic Abstract, Accession Number 36097R, discloses 1-(.beta.-pyrrolidino-ethyl)-2-(p-ethoxyphenylthio)-benzimidazole as an analgesic.
Derwent Basic Abstract, Accession Number 44380R, discloses 2-methylthio-1(3'-nicotinyl)-benzimidazole as an antiinflammatory agent.
Derwent Basic Abstracts, Accession Numbers 15402U, 60320W and 17936U, disclose mercapto-benzimidazolyl (thio) ureas and 1-acyl-2-(phenylcarbamoyl-alkylthio)benzimidazoles useful as anthelmintics.
Derwent Basic Abstract, Accession Number 32075U, discloses 1-(bis-(2-chloroethyl)carbamoyl-benzimidazoles with potential cytostatic and immunosuppressant activity.
Derwent Basic Abstract, Accession Number 61208W, discloses 2-(benzimidazol-2-ylthio)succinic acids which are useful as antiinflammatory and analgesic agents and as chelating agents.
Derwent Basic Abstracts, Accession Number 68107W, 75825W, 02854Y, 02855Y, 08362Y, 08363Y and 11905Y, disclose benzimidazolyl-piperidine derivatives with psychotropic properties.
Derwent Basic Abstract, Accession Number 86748W, discloses antiinflammatory, N-substituted-mercaptobenzimidazoles.
Derwent Basic Abstract, Accession Number 74426A, discloses 2-alkylthio-5-phenoxy or phenylthio-benzimidazole derivatives which are useful in anthelmintics.
Derwent Basic Abstracts, Accession Numbers 79478B and 82975X, disclose substituted pyridyl-sulphinyl-benzimidazoles are gastric acid secretion inhibiting agents.
Derwent Basic Abstract, Accession Number 54809E, discloses pyridyl substituted 2-hydroxy or mercapto benzimidazole derivatives which are useful as cardiotonic agents.
Derwent Basic Abstract, Accession Number 27874K, discloses 2-substituted-pyridinyl methylthio-benzimidazole derivatives which are useful as inhibitors of gastric acid secretion.
Derwent Basic Abstract, Accession Number 54214K, discloses 4-methoxy-2-pyridylmethyl)thio- and -sulphinyl benzimidazole derivatives for reducing secretion of stomach acid and therefore treating ulcers and gastritis.
Derwent Basic Abstract, Accession Number 83-724637, discloses synergistic anthelmintics containing 2-methylthio- or 2-methylsulphinyl-5-chloro-6,2,3-dichloro-phenoxy-benzimidazole with another benzimidazole.
Chemical Abstracts 71:49852j (1969) discloses 1,1,1-trichloro-5-(2-benzothiazolylthio)pentane; 1,1,1-trichloro-5(2-benzimidazolythio)-pentane; 1,1,1-trichloro-5-(2-benzoxazolylthio)-pentane; 1,1-dichloro-3-(2-benzothiazolylthio)propene; 5-(2-benzothiazolylthio)pentanoic acid; 5-(2-benzoxazolylthio)pantanoic acid and 2-(2-benzothiazolylthio)ethanoic acid.
U.S. Pat. No. 3,792,170 discloses lower alkyl sulphinyl aryl aralkanoic acids which are useful as analgesics and antipyretics.
Derwent Basic Abstract, Accession Number 39933B, discloses antirheumatic, antiphlogistic zinc heterocyclic derivatives, e.g., zinc bis-(mercaptothiazole).
Derwent Basic Abstract, Accession Number 79347T, discloses isothiocyano-substituted benz(ox, thi or imid)azoles which are useful as anthelmintics. Derwent Basic Abstract, Accession Number 44280W, discloses biocidal 2-nitro-6-hetero-cyclythio-4-trifluoromethyl-benzonitriles such as the 6-(2-benzoxazolythio) compound.
Derwent Basic Abstract, Accession Number 66789T, discloses 5-nitro-2-thiazolyl sulphides and sulphones with antifungal activity.
Derwent Basic Abstract, Accession Number 01014X, discloses alpha-substituted-gamma-butyrolactone derivatives which have central nerve, antiinflammatory and antifungal activities.
Derwent Basic Abstract, Accession Number 66847Y, discloses (1,4)-disubstituted piperidine and piperazine derivatives for use as antiallergic agents.
Derwent Basic Abstract, Accession Number 52514D, discloses benzo-thiazolone derivatives having antiinflammatory, analgesic, antiallergic activities and also CNS-inhibitory activity.
Derwent Basic Abstract, Accession Number 29,132, discloses antimicrobial 2-phenyl-maleimides and succinimides.
Derwent Basic Abstract, Accession Number 32863R, discloses pyridylalkylthio- and pyridylalkyl-oxy-benzazoles which are useful as bacteriostats, anthelmintics and antiiflammatories.